Studies on Development of Benign Technologies for Some Organic Transformations with Organic Catalysts and Synthesis of the Substituted Neocryptolepines as Drug Candidates of Antimalarial Agents

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(1)Studies on Development of Benign Technologies for Some Organic Transformations with Organic Catalysts and Synthesis of the Substituted Neocryptolepines as Drug Candidates of Antimalarial Agents. September, 2012. Zhen-Wu Mei. Graduate School of Natural Science and Technology (Doctor Course) OKAYAMA UNIVERSITY.

(2) CONTENTS. Chapter 1. Introduction and General Summary. Chapter 2.. ……………………………….1. High Performance and Selective Oxidation Method for Secondary Alcohols by Use of Organic Catalyst. ……………………………29. Chapter 3. Green Procedure for Preparation of Carboxylic Acid by TEMPO Oxidation of Primary Alcohols. ………………………………......53. Chapter 4. Synthesis and Evaluation of Novel Neocryptolepine Derivatives for Developing Antimalarial Agents ………..…………..……………..69. Publication List. Acknowledgment. ………………………………………………………………134. …………………………………………………………….140.

(3) Okayama University 2012.9. Chapter 1. Introduction and General Summary. -1-.

(4) Okayama University 2012.9. 1. Introduction. In the last few years there has been placed a strong emphasis on development of so-called ''Green Chemistry'', which has been employed to protect the environment from pollutants. Many toxic reagents are used in the daily laboratory reactions and their resulting by-product can cause environmental pollution. These chemicals are frequently discharged to the stream of water or air, thus cause either water, air or soil pollutions. As a result, these cause a great threat to our aquatic life as well as different kind of diseases like cancer, chronic lung disease and malaria. So we have two major problems, to minimize this man-made pollution and to explore new drugs to meet the needs of drug-resistant diseases which due to environmental etiologies. With the rapid industrial development, environmental problems became increasingly serious. Oxidation reactions are among the most numerous and useful of the industrial processes and, at the same time, the most hazardous and polluting ones. They often occur with high E (environment)-factor, defined by Sheldon as the mass of waste, corresponding to all compounds used which are not incorporated in the product, per mass unit of product.1 The oxidation of alcohols to their corresponding carbonyl compounds is a pivotal transformation in organic chemistry.2 Traditionally, oxidation of alcohols is carried out using stoichiometric amounts of metallic oxidants notably chromium(VI) reagents,3. permanganates,4. and. ruthenium(VIII). oxide,5. which. produce. environmentally unacceptable heavy metal wastes.6 Since the goal of avoiding the use of environmentally unfriendly or toxic metals has always been considered extremely important, the development of efficient metal-free oxidation catalysts has been very actively pursued in the field of organocatalysis. Many of the organic catalysts identified in recent years have also been immobilized on different supports, such as Swern Oxidation, Corey-Kim Oxidation and Dess-Martin oxidation have been developed. over. the. past. several. -2-. decades.7. Among. these,. the.

(5) Okayama University 2012.9. 2,2,6,6-tetramethyl-1-piperidinyloxy [TEMPO (2), a nitroxyl radical] (Figure 1) catalyzed oxidation method has attracted attention in many areas of synthetic organic chemistry because it enables the use of various safe bulk oxidants, thereby enabling a safe and extremely efficient oxidation of alcohols with considerable operational simplicity.8-9. Figure 1. Structures of organic nitroxyl radicals. N O. N O. N O. 1. 2. 3. Organic nitroxyl radicals, such as conjugated nitroxyl radical the diphenylnitroxyl radical (1) have been known since the early 20th century.10 The stable, non-conjugated nitroxyl radicals TEMPO (2) and di-tert-butylnitroxyl (3) were first reported by Lebedev and Kazarnovskii. 11. and Hoffmann and Henderson, 12 in 1960 and 1961,. respectively. The unpaired electron in these radicals is delocalized over the nitrogen-oxygen bond, as shown in Figure 1, and this accounts for their high stability. Thus, radicals of this type can be stored for long periods of time without decomposition. They dissolve in both polar and non-polar solvents to form brightly colored solutions, e.g., TEMPO is bright orange.. Scheme 1. Oxidation and reduction of TEMPO. Oxidation. Oxidation. N OH 4. Reduction. N O 2. Reduction. N O 5. Such nitroxyl radicals (TEMPO) give on oxidation the oxoammonium ion (5) and. -3-.

(6) Okayama University 2012.9. on reduction hydroxylamines (4) (Scheme 1). Nitroxyl radicals are weak oxidants, and by themselves they are limited to the oxidation of ascorbic acid and phenylhydrazine.13-14 In these redox reactions, TEMPO is converted to the corresponding hydroxylamine. In contrast, when the oxoammonium ion is generated by oxidation of the nitroxyl radical TEMPO, a much stronger oxidant will be resulted, which is capable of oxidizing a large variety of substrates. The important oxidative transformations effected by the oxoammonium ion are shown in the form of a rosette in Scheme 2.15. Scheme 2. A rosette of the important oxidative transformations effected by the oxoammonium ion (5).. OR OR. ArCN / ArCHO. R2S. O. OR ArCH2NH2. O. R2S. O. R3P=O. OH R3P. O. R. R R. R O. N O 5. RCH2OH RCHO / RCOOH. O ArCH2OR R. OH OH. R2CHOH. R2C=O. ArC(C=O)OR / ArCHO. O R. O. Based on these facts, we can summarize that TEMPO is an environmentally friendly catalyst, because it could be a remarkably stable radical, easily handling, and recyclable and stoichiometric transforming ability for alcohol oxidation. Meanwhile, exploring new drugs to meet the needs of drug-resistant diseases is still a hot topic in the medicinal chemistry. Especially malaria remains the most. -4-.

(7) Okayama University 2012.9. devastating disease in the tropical and subtropical regions where both developing and non-industrialized nations, with staggering infection and mortality statistics. According to the World Health Organization (WHO), this disease led to about 216 million malarial infected cases in 2010, and approximately 0.7 million died due to the non-availability of proper treatment, involving mostly children under 5 years old.16 Human malaria is caused by five species of the genus Plasmodium falciparum, P. vivax, P. ovale, P. malariae and P.knowlesi. The falciparum species is responsible for the majority of human deaths from malaria. Human suffers malaria when bitten by the female of any one of the 60 species of Anopheles mosquito.17 The life cycle of the parasite from mosquito to human blood, to the human liver, back to the blood, and back to another mosquito is well-known (Figure 2).17-18. Figure 2. Malaria life cycle Human Liver Stages. Mosquito Stages. Exo-erythrocytic (hepatic) Cycle:. Sporogonous Cycle:. Human Blood Stages. P. falciparum. Erythrocytic Cycle: Gametocytes P. vivax P. ovale P. Malariae P. knowlesi. Despite the worldwide public health impact of malaria, neither the mechanism by which the Plasmodium parasite detoxifies and sequesters haem, nor the action of. -5-.

(8) Okayama University 2012.9. current antimalarial drugs is well understood. A proposal mechanism for Plasmodium parasite of detoxification process was reported that parasite converts toxic haem into a non-toxic haemozoin by a mechanism known as haemozoin formation (Figure 3). The toxic haem groups released from the digestion of the haemoglobin of infected red blood cells are oxidized into nontoxic -haematin dimer by axial ligation of one propionic acid of each Fe(III)-protoporphyrin-IX unit and the -haematin dimer are aggregated into an insoluble material called haemozoin or malaria pigment.19. Figure 3. Proposed mechanism of malarial detoxification process. Haem (Toxic). -haematin. Haemozoin (Nontoxic). Several types of antimalarial drugs are reported to exhibit antimalarial activity by enhancing free haem toxicity through the inhibition of haemozoin formation. The families belonging to this category are quinoline, zaoles, methylenebule, xanthones, isonitriles and their derivatives. Amongst of them, quinoline and its derivatives represent a very important class of antimalarial drugs that function by targeting the parasite specific haemoglobin breakdown pathway.20 Important members of this class are chloroquine (CQ), amodiaquine, amopyroquine, mepacrine, quinine, epiquinine, quinidine and bisquinoline, structures and antimalarial activities of which are shown in Figure 4.21. -6-.

(9) Okayama University 2012.9. Figure 4. Structures and antimalarial activitiesa of quinoline and its derivatives OH N. HN. Cl. N. Cl. HO. IC50 = 5.3 nM (CQS) IC50 = 11.5 nM (CQR) H. H. N. H. N. H. H3CO. N H. IC50 = 3471 nM (CQS) IC50 = 1179 nM (CQR). Me. Me NEt2. HN. N. N. (CH2)n. HN. NEt2. N. Bisquinolines (n=8-12) IC50 = 123 nM (CQS) IC50 = 25 nM (CQR). Quinidine IC50 = 21.5 nM (CQS) IC50 = 50.6 nM (CQR) a. OH. Epiquinine. IC50 = 34.2 nM (CQS) IC50 = 81.2 nM (CQR) H. HO. N. N. N Quinine. Mepacrine IC50 = 12.9 nM (CQS) IC50 = 43.3 nM (CQR). H. H. H3CO. H3CO Cl. N Amopyroquine. IC50 = 7.8 nM (CQS) IC50 = 18.5 nM (CQR). N. N. HN. Amodiaquine. Chloroquine IC50 = 14.0 nM (CQS) IC50 = 192.1 nM (CQR). HN. N. HN. Cl. N. OH. CQS, chloroquine sensitive P. falciparum; CQR, chloroquine resistant P. falciparum.. Chloroquine (CQ) is a weakly basic amphipath and accumulated inside the food vacuole. It interacts with the μ-oxo dimer form of oxidized haem and prevents the haemozoin formation. The π–π interaction between chloroquine and the electronic system of haematin governs the formation of adducts. Free haem and haem-chloroquine complexes kill parasites by inducing oxidative stress and this oxidative stress may lead to peroxidation of parasite membrane lipids, damage of DNA, oxidation of protein and finally parasite death.22 Malaria is still a major public health problem mainly due to the development of resistance by the most lethal causative parasitic species, Plasmodium falciparum to the mainstay drugs like CQ because of its remarkable therapeutic effect and low. -7-.

(10) Okayama University 2012.9. cost.23 Despite the introduction of the artemisinin-based combination therapies (ACTs), new drugs with unique structures and mechanism of action are urgently required to treat sensitive and drug-resistant strains of malaria.. Figure 5. Antimalarial agents from natural products H O O O HO. HO H. OH. H. H. N O. H3CO. O. O. O. N. Artemisinin (Artemisia annua ). Quinine (Cinchona succirubra ). Clausarin (Clausena harmandiana ). O. O O. O. O OCOCH3. H N. N O. O. H N. N. N OMe O. N. OMe O S. Gedunim (Cedrela odorata). Dolastatin 10 (Sea hare D. auricularia). Meanwhile, natural products are still important resources for discovery of new drugs for antimalarial (Figure 5). Compounds containing novel structure from natural origin also represent a major source for the discovery and development of new drugs for several diseases. Many naturally occurring compounds, including the major alkaloid cryptolepine (6) and minor alkaloid neocryptolepine (7), were isolated from the roots of the West African plants Cryptolepis sanguinolenta (Figure 6). Both of the two tetracyclic heteroaromatic compounds are linearly fused indoloquinolines and exhibit a promising antiplasmodial activity both against chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) P. falciparum.24-25 Further experiments have also indicated that cryptolepine inhibits the β-haematin formation which is responsible for. -8-.

(11) Okayama University 2012.9. the treatment of malaria infections, and also has a cytotoxicity due to a DNA intercalation activity.26-27 Therefore, neocryptolepine could be selected as the lead compound for the development of new antimalarial agents because of its lower affinity for DNA intercalation and topoisomerase II compared to cryptolepine.. 28. Figure 6. Structures of cryptolepine and neocryptolepine.. A. B N Me. N C. 11. A. B C N6 N 5 Me. 2 D. 3. 4. 9. 10. 1. 8. D 7. 7, Neocryptolepine. 6, Cryptolepine. Based on these backgrounds, in this thesis, the author has engaged with three research topics toward the environmentally friendly technologies for organic transformations with organic catalysts and design and synthesis of neocryptolepine derivatives for antimalarial agents: (1). High Performance and Selective Oxidation Method for Secondary Alcohols by Use of Organic Catalyst. (2). Green Procedure for Preparation of Carboxylic Acid by TEMPO Oxidation of Primary Alcohols. (3). Synthesis and Evaluation of Novel Neocryptolepine Derivatives for Developing Antimalarial Agents. -9-.

(12) Okayama University 2012.9. In Chapter 2, the author described a combination of Py∙HBr3 as a co-oxidant and the electronically activated TEMPO as a recyclable catalyst is useful for oxidation of not only common alcohols, but also of the electron-deficient secondary alcohols such as ArCH(OH)CFCl2 (Scheme 3). And the enhanced reactivity of the electronically activated TEMPOs was rationalized by the characterization of their redox properties.. Scheme 3. Reaction paths of alcohol oxidation using EWG-TEMPO and Py.HBr3 X OH Ar Hal 8. O EWG Hal Path A. .. Py HBr N O. 11 5. Path B. X. O Ar Hal 9. EWG Hal. OH N O. Py . HBr3 10. 2. X = ElectronWithdrawing Group Path A, Mainly about electron-deficient secondary alcohols; Path B, Possible about electron-rich alcohols.. Oxidation of alcohols to their corresponding carbonyl compounds is a fundamental reaction in synthetic organic chemistry.29 In this Chapter, the author focused on the TEMPO oxidation of alcohols in combination with a non-toxic co-oxidant since TEMPO is recoverable organic catalyst after the oxidation. Mostly important is that TEMPO oxidation is environmentally friendly procedure in organic chemistry, because TEMPO oxidations are performed in a catalytic manner as a non-metallic reagent. The remarkable acceleration can be explained by the proposed catalytic cycle shown in Scheme 4. TEMPO radical is first oxidized by co-oxidant (Py∙HBr3) to N-oxoammonium ion, which rapidly oxidizes the alcohol to the ketone and gives a molecule of the hydroxylamine, finally the hydroxylamine is oxidized to a TEMPO radical and completing the catalytic cycle.. - 10 -.

(13) Okayama University 2012.9. Scheme 4. Proposed mechanism of the TEMPO Oxidation. OH PyHBr PyHBr3. R1. N O. R2. Alcohol. N-Oxoammonium ion. Co-oxidant. N O N O. O. R2 R1 Intermediate H. TEMPO Radical. O H. R1 N OH. R2. Ketone. Hydroxylamine. However, one distinguishing feature of the TEMPO-based method is its capability for the selective oxidation of primary alcohols in the presence of secondary alcohols.30 The rationale behind such a feature is its reaction mechanism and the catalyst structure of that used, where four methyl groups flanking the nearby catalytic center play key roles in preventing bulky substrates from forming the key intermediate, which collapses to a carbonyl compound and the hydroxylamine (Scheme 4). Paradoxically, TEMPO is inefficient in the oxidation of structurally hindered secondary alcohols, posing a problem in the oxidation of alcohols. Although several modifications by reface of the reaction site of TEMPO have been devised in order to avoid steric repulsion in the nucleophilic addition of alcohol to the N-oxoammonium intermediate, as exemplified by Shibuya et al.31 Examination of effects of the substituent at the C-4 position of TEMPO is still scarce today, so the author examined the effect of the substituents at the C-4 position to increase TEMPO reactivity in oxidation of secondary alcohols by testing four kinds of appendages (X) at the C-4. - 11 -.

(14) Okayama University 2012.9. position (Scheme 5). Among these, TEMPOs (2c, 2d and 2e) are substituted with electron-withdrawing group (EWG) at C-4 position.. Scheme 5. Increasing reactivity of TEMPO EWG Modification O. N. N O AZADO. N O. 2, TEMPO. Shibuya et al. J. Am. Chem. Soc. 2006, 128, 8412-8413.. 4-EWG-TEMPO. Inductive effect X = Appendages 2a: X = H b: X = MeO. O . N . c: X = C6H5CO2. EWG. d: X = 4-CF3C6H4CO2 e: X = C6F5CO2. On the other hand, bromine and its amine complexes are capable of oxidizing alcohols, producing the corresponding carbonyls and various methods and bromine-intercalated reagents have been developed (Table 1).32 In this chapter, the author examined the use of pyridinium hydrobromide perbromide (Py∙HBr3) as a co-oxidant, since this commercially available and stable reagent is less expensive than R4NBr3 (tetrabutylammonium tribromide, Bu4NBr3), and more advantageously polymer-supported pyridinium hydrobromide perbromide (Poly(N-vinylpyridinium)hydrotribromide) is now available, though its oxidizing ability is not well characterized until now.33. - 12 -.

(15) Okayama University 2012.9. Table 1. Bromine and its derivatives are capable of oxidizing alcohols. Co-oxidants. Reactions. Ref. 32 J. Am. Chem. Soc. 1949, 71, 2829–2833. O. Br2. OH. J. Am.Chem. Soc. 1972, 94, 6116–6119. H. O OH. Br2 + HNO3 + O2. Synlett 2004, 2203–2205. H 96% Py • TFA. OH. N Br N Br. J. Org. Chem. 1992, 57, 1600–1603. O 97%. Br3 N. Br N. Br. N. N. OH. n. O. 97%. Tetrahedron Lett. 2006, 47, 6635–6636. Polymeric DABCO-Br2 complex. In this Chapter, the author described that the oxidizing system which carried out by combination of 4-CF3C6H4CO2-TEMPO and Py∙HBr3 in the two phase system of CH2Cl2aqueous NaHCO3 was useful for oxidation of common alcohols and some structurally hindered secondary alcohols, but also of the electron-deficient secondary alcohols (Scheme 6), and attained good yields (69%~94%).. Scheme 6. Oxidation of polyhaloalkylmethanols (8) with a combination of 2d and Py.HBr3. OH Ar. EWG Hal Hal. O 2d / Py.HBr3. Ar. CH2Cl2 / NaHCO3. EWG Hal Hal 9. 8. Yields: 69% ~ 94%. In Chapter 3, the author described a benign method for primary alcohol-carboxylic acid conversions with TEMPO-mediated oxidation in a biphasic system composed of aqueous layer and slightly miscible ether solvent, such as tetrahyrdopyran (THP), which is low harmful solvent and shown more efficient compared with cyclopentyl methyl ether (CPME), tetrahydrofuran (THF), diisopropyl ether, methyl tert-butyl ether and CH2Cl2. And following easily available co-oxidants such as Py∙HBr3,. - 13 -.

(16) Okayama University 2012.9. Bu4NBr3,. and. electrooxidation. were. successfully. applied. to. generate. N-oxoammonium species as a recyclable catalyst, especially Py∙HBr3. The most favorable combination of TEMPO and Py∙HBr3 in THPaqueous NaHCO3 biphasic system was useful for oxidation of various primary alcohols including aromatic, aliphatic, and carbohydrate derivatives, and yielded the corresponding carboxyl acids.34 Synthesis of carboxyl group-containing compounds become an important organic chemistry, as the carboxyl group is widely found not only in natural compounds, such as pyruvic acid and biotin etc., but also common in drugs (Figure 7), 35 which can act as hydrogen bond acceptor in various ways, or as a hydrogen bond donor.36 On the other hand, oxidation of alcohols to the corresponding carboxylic acids is one of a fundamental operation in organic chemistry.37. Figure 7. Structures of carboxyl group containing compounds O. O. HOOC. B. O O. O. HN H. B: Nucleoside (A,U,C,G). COOH Pyruvic acid (A metabolic intermediate). NH H. Nucleic Acid (Composition of DNA/RNA). Biotin (A cell growth factor). O. COOH. N HOOC. O. COOH. S. MeO. COOH COOH. BAY X1005 Dehydromucic Acid (Antifungal for treatment of autism) (Leukotrienc receptor antagonists and lipoxygenase inhibitors). Naproxen (Anti-inflammatory drug). Although many approaches for oxidation of alcohols to the corresponding carboxylic acids have been developed, environmentally friendly procedure of alcohol-carboxylic acid transformations is still a hot topic in chemistry.38 The author further his endeavor on TEMPO-mediated oxidation of alcohols with combination of electronically activated TEMPO and co-coxiant39 and replace harmful solvent. - 14 -.

(17) Okayama University 2012.9. (CH2Cl2) by ethereal solvent like THP. THP is an important solvent in organic chemistry, consisting of a saturated six-membered ring containing five carbon atoms and one oxygen atom. THP shows medial physics between 1, 4-dioxane and THF, except for the solubility in water, which has a solubility of only 2.58.1 wt% in water (Table 2). Although THP's hydrophobicity is not as good as benzene, it could be considered as an easy to be separated from water. Furthermore, Yasuda, H et al have recently demonstrated the excellent stability of THP towards auto-oxidation compared with THF, as a result of their study on tributyltin hydride-mediated radical cyclizaion.40 The author employed THP as the organic layer of a two-phase system in TEMPO-mediated oxidation of alcohols since THP could be less likely to form peroxide with oxygen during TEMPO oxidation.. Table 2. Physic properties of THP and other solvents Solvent. THF. THP. 1,4-DIOX. Benzene. O. Structure. O. O. O. o. 65. 88. 102. 80. mp ( C). o. 109. 45. 12. 5.5. Azeotropy o ( C/H2O(wt%)). 64/6. 75/12. 88/18. 75/15. Solubility (/H2O(wt%)). /. 2.5/8.1. /. 0.1/0.1. Dielectric Constant o ( C). 7.58. 5.61. 2.21. 2.28. bp ( C). Subsequently, following ethereal solvents were compared with THP (Yield: 91%). - 15 -.

(18) Okayama University 2012.9. as organic layer by combination of TEMPO and Py∙HBr3 in oxidation of 12 to 13 (Scheme 7): CPME (Yield: 80%), THF (Yield: 80%), diisopropyl ether (Yield: 67%), methyl tert-butylether (Yield: 89%), CH2Cl2 (Yield: 77%). Among these solvents, THP should be the best because of its high yield.. Scheme 7. Oxidation of primary alcohol with a combination of 4-BzO-TEMPO and PyHBr3 OH. 4-BzO-TEMPO (2c) / PyHBr3. OH. Solvent NaHCO3. OBz. O. 12. N O. 13. 2c, 4-BzO-TEMPO. Product 13, %. Solvent CH2Cl2. 77. THP. 87 (91)a. CPME. 80. DIPE. 67. THF. 80. OMe O THP a. CPME. O DIPE. O THF. Number in parenthesis is the yield obtained with a large scale operation (12, 15 mmol). Furthermore, the present method by combination of TEMPO and Py∙HBr3 in THPaqueous NaHCO3 biphasic system was applied not only to aliphatic primary alcohols including acyclic and cyclic structures but also to aromatic and hetero aromatic alcohols, some of which are of significant synthetic value. Such as oxidation of. 5-(hydroxymethyl)-2-furaldehyde. (HMF),. leads. selectively. to. 5-formyl-2-furancarboxylic acid (FFA), useful as a precursor of 2,5-furandicarboxylic acid (FDCA). This method makes it much simple to synthesize FFA compared with other methods reported by Lewkowski J et al,41 which were carried out by formation 2,5-diformyl furan (DFF) or 5-hydroxymethyl-2-furoic acid (HMFA) as intermediate (Scheme 8).. - 16 -.

(19) Okayama University 2012.9. Scheme 8. Oxidation routes of HMF to FDCA OHC. O. CHO. DFF. O HO. THP, NaHCO3. CHO. O. HOOC. CHO. HOOC. O. COOH. 4-BzO-TEMPO, PyHBr3 FFA. HMF. O. FDCA. COOH. HO HMFA. In Chapter 4, the author described synthesis and evaluation of novel neocryptolepine derivatives for developing antimalarial agents. Since the spread of Plasmodium falciparum strains resistant to CQ is dramatically increasing over these years, new agents for antimalarial treatment is still urgently need to feed the preclinical pipeline. During the structure-activity relationship (SAR) study of CQ (Figure 8),42 the author knew that elaborate other molecules which are found to form π–π complexes with Fe (III)PPIX and which inhibit -haematin formation so as to arrive at novel antimalarials by semirational design. These findings are also of considerable interest when combined with the recent structure function investigations of Krogstad and co-workers43-44 which have shown that changes in the length of the aminoalkyl side chain have little influence on activity against chloroquine-sensitive strains. of P. falciparum. but. a profound. influence on activity against. chloroquine-resistant strains of the parasite. And further exploration also suggested that sufficiently large changes in the side chain alone could overcome the chloroquine-resistance. without. having. to. make. changes. in. the. 4-amino-7-haloquinoline template responsible for the Fe (III) PPIX complexation and inhibition of β-haematin formation.42. - 17 -.

(20) Okayama University 2012.9. Figure 8. Proposed structure-function relationships in chloroquine Inhibition of -haematin formation N. HN 5. 4. 6. Cl. 3. N. 7 8. 2. 1. Weak bases: assist in drug accumulation via pH trapping. Fe(III)PPIX complexing group. Based on these facts, the author synthesized and evaluated natural product derivatives based on neocryptolepine core, which is minor indolequinone alkaloid from the roots of the West African plants cryptolepis sanguinolenta. The author designed various novel neocryptolepine derivatives for improving antimalarial activity by modifications of the side chain at the C-11 position of neocryptolepine core under varying the substituents at the C-2 position with electron-withdrawing or electron-donating groups, and for further variation, the aminoalkylamino substituents were transformed into the corresponding acyclic or cyclic carbamates or thiocarbamates (Scheme 9).. - 18 -.

(21) Okayama University 2012.9. Scheme 9. Modification of neocryptolepine analogues 1 mS. O. 2 R3. N. 3. A 4. 11. 9. 10. 8. D. B C N6 N 5 Me. NH-(CH2)3-NH. SO2R4. 7 N. N. Neocryptolepine. HN. N. O. N m = 1, 2. NH-(CH2)3-NH. R2. R5. R1 N. N. N. N. S O. N. R3. X NH-(CH2)n-NH R1 = H, Cl, Br, F, CF3, NO2, MeO R2 = NH-(CH2)n-NH2, n = 3, 6. HN. N. NH-R6. R1 N. N. N X = O, S. These modified neocryptolepine derivatives were tested for antimalarial activity against CQR (K1) and CQS (NF54) of Plasmodium falciparum in vitro. The evaluation also included cytotoxicity toward mammalian L6 cells. All the synthesized neocryptolepine derivatives showed potent antiplasmodial activities against CQR (K1) and CQS (NF54) in vitro. Some tested compounds showed more potent activity than CQ (Figure 9 and Table 3).. - 19 -.

(22) Okayama University 2012.9. Figure 9. Structures of some modified neocryptolepine derivatives. S O. S. N N. O. S. N. O. N. Cl HN. HN. N. N. N. 14. Cl HN. N. N. 15. O N H. N. 16. O. S. O S. N H. N H. N H HN. HN. HN. N H. R N. N. N. N. N. 19 a R = H, b R = Cl, c R = NO2. 18. 17. Table 3.. N. Antimalarial activities of the modified neocryptolepine derivatives a. a. b. CQS (NF54). CQR (K1). Cytotoxicity (L6). SI. SI. RI. IC 50 (nM). IC 50 (nM). IC 50 (nM). (L6/NF54). (L6/K1). (K1/NF54). 14. 54.9. 143.2. 3551. 64.7. 24.8. 2.6. 15. 52.4. 38.8. 3359. 64.1. 86.6. 0.7. 16. 26.6. 21.3. 1099. 41.3. 51.6. 0.8. 17. 63. 123.7. 65.2. 1.0. 0.5. 2.0. 18. 9.1. 111.5. 1228. 134.9. 11.0. 12.3. 19a. 21.3. 9.4. 1244. 58.4. 132.3. 0.4. 19b. 2.2. -. 3079. 1400. -. -. 19c. 2.1. -. 2732. 1301. -. -. CQ. 9.4. 209.5. -. -. -. 22.3. a,. Selectivity Index is the ratio of IC50 for cytotoxicity versus antiplasmodial activity (L6/P.f.). b,. Resistance Index is the ratio of IC50 for the resistant versus the sensitive strain (K1/NF54). - 20 -.

(23) Okayama University 2012.9. As shown in Table 3, among these tested compounds, 19b showed a 4 times more potent activity than CQ for CQS (NF54) with an IC50 of 2.2 nM and a selectivity index of 1400, similarly high antimalarial activity was shown by 19c. Furthermore, 19a showed a 22 times more potent activity than CQ for CQR (K1) with an IC50 of 9.4 nM, an electivity index of 132.3 and a resistance index of 0.4 with K1/NF54. These present findings are sufficient to establish that the methodical variation of the side chain of the neocryptolepine core provides a promising entry point toward affordable haem-targeted antimalarials that overcome the ever-increasing problem of worldwide drug resistance.. - 21 -.

(24) Okayama University 2012.9. 2. General Summary. In conclusion, the author summarized the present contributions as follows: (1) A high performance oxidation method of alcohols with TEMPO substituted with an EWG at the C-4 position, which is useful for the electron-deficient secondary alcohols such as ArCH(OH)CFCl2, has been developed by using Py∙HBr3 as a co-oxidant. Reactivity of Py∙HBr3 was discussed in terms of efficiency and selectivity in comparison with similar bromine compounds such as Bu4NBr3, and the method was easily extended to the polymer supported bromine reagents as a co-oxidant. Inductive activation of TEMPO by the appendage of electron-withdrawing group at the C-4 position was shown to facilitate the reaction rate, which was rationalized by measuring the cyclic voltammetry of the 4-substituted TEMPOs. (2) The author developed an efficient primary alcohol-carboxylic acid conversion by employing TEMPO oxidation in ethereal solvent such as THPaqueous layer instead of often used harmful solvents like CH2Cl2aqueous layer. During the TEMPO mediated oxidation of primary alcohols, many easily available oxidants, such as Py∙HBr3 and electrooxidation with bromide ion were successfully applied as co-oxidants. The method could easily be applied to various primary alcohols including aromatic, aliphatic, and carbohydrate derivatives, some of which are of significant synthetic value. (3) A novel series of new neocryptolepine derivatives have been developed by systematically varying the 2-substituents of the neocryptolepine core and simply modifying the terminal amino group of the C-11 aminoalkylamino side chain. All the synthesized neocryptolepine derivatives were tested for antimalarial activity against CQR (K1) and CQS (NF54) of Plasmodium falciparum in vitro and cytotoxicity toward mammalian L6 cells. All tested compounds showed potent antiplasmodial activities against CQR (K1) and CQS (NF54) in vitro and some compounds, such as 19a-c, showed much greater potency than CQ. These present findings are sufficient to. - 22 -.

(25) Okayama University 2012.9. establish that the methodical variation of the side chain of the neocryptolepine core provides a promising entry point toward affordable haem-targeted antimalarials that overcome the ever-increasing problem of worldwide drug resistance.. - 23 -.

(26) Okayama University 2012.9. References. 1. R. A. Sheldon, Consider the environmental quotient. Chemtech. 1994, 3, 38–47. 2. (a) M. F. Schlecht, In Comprehensive Organic Synthesis, (Eds.: B. M. Trost, I. Fleming, S. V. Ley), Pergamon: Oxford, 1991, Vol 7, pp 251–327. (b) Modern Oxidation Methods, (Ed.: J.-E. Bäckvall), Willey-VCH: Weinheim, Germany, 2004. 3. (a) G. Cainelli, G. Cardillo, Chromium Oxidants in Organic Chemistry, Springer-Verlag, Berlin, 1984. (b) S. Patel, B. K. Mishra, Tetrahedron 2007, 63, 4367. 4. (a) S. L. Regen, C. Koteel, J. Am. Chem. Soc. 1977, 99, 3837. (b) F. M. Menger, C. Lee, Tetrahedron Lett. 1981, 22, 1655. 5. W. P. Griffith, Chem. Soc. Rev. 1992, 21, 179. 6. J. March, Advanced Organic Chemistry, John Wiley: New York, 1992, pp 1167. 7. (a) S.-I. Ohsugia, K. Nishidea, K. Oonob, K. Okuyamab, M. Fudesakaa, S. Kodamaa, M. Node, Tetrahedron 2003, 59, 8393–8398. (b) S. D. Meyer, S. L. Schreiber, J. Org. Chem. 1994, 59, 7549–7552. (c) J. S. Yadav, B. V. S. Reddy, A. K. Basak, A. V. Narsaiah, Tetrahedron 2004, 60, 2131–2135. 8. (a) A. E. de Nooy, A. C. Besemer, H. van Bekkum, Synthesis 1996, 1153–1174. (b) R. A. Sheldon, I. W. C. E. Arends, Adv. Synth. Catal. 2004, 346, 1051–1071. 9. (a) J. A. Cella, J. A. Kelly, E. F. Kenehan, J. Org. Chem. 1975, 40, 1860–1862. (b) M. F. Semmelhack, C. R. Schmid, D. A. Corte´s, C. S. Chou, J. Am. Chem. Soc. 1984, 106, 3374–3376. (c) P. L. Anelli, C. Biffi, F. Montanari, S. Quici, J. Org. Chem. 1987, 52, 2559–2562. (d) P. L. Anelli, S. Banfi, F. Montanari, S. Quici, J. Org. Chem. 1989, 54, 2970–2972. (e) A. De Mico, R. Margarita, L. Parlanti, A. Vescovi, G. Piancatelli, J. Org. Chem. 1997, 62, 6974–6977. (f) C. Biom, A. S. Magus, J. P. Hildebrand, Org. Lett. 2000, 2, 1173–1175. (g) H. Bjørsvik, L. Liguori, F. Costantino, F. Minisci, Org. Proc. Res. Dev. 2002, 6,. - 24 -.

(27) Okayama University 2012.9. 197–200. (h) R. A. Miller, R. S. Hoerrner, Org. Lett. 2003, 5, 285–287. (i) R. Liu, X. Liang, C. Dong, X. Hu, J. Am. Chem. Soc. 2004, 126, 4112–4113. 10. H. Wieland, M. Offenbacher, Ber. Dtsch. Chem. Ges. 1914, 47, 2111. 11. O. L. Lebeder, S. N. Kazarnovskii, Zh. Obshch. Khim. 1960, 30, 1631; Chem. Abstr. 1961, 55, 1473. 12. A. K. Hoffmann, A. T. Henderson, J. Am. Chem. Soc. 1961, 83, 4671. 13. C. M. Paleos, P. Dais, J. Chem. Soc., Chem. Commun. 1977, 345. 14. T. D. Lee, J. F. W. Keana, J. Org. Chem. 1975, 40, 3145. 15. (a) R. Siedlecka, J. Skarzewski, Synthesis 1994, 401. (b) D. H. Hunter, D. H. R. Barton, W. J. Motherwell, Tetrahedron Lett. 1984, 25, 603. (c) T. Inokuchi, S. Matsumoto, T. Nishiyama, S. Torii, J. Org. Chem. 1990, 55, 462. (d) T. Miyazawa, T. Endo, Tetrahedron Lett. 1986, 27, 3395. (e) N. S. Cho, C. H. Park, J. Korean Chem. Soc. 1995, 39, 657; Chem. Abstr. 1995, 123, 313502. (f) Y. Kashiwagi, H. Ono, T. Osa, Chem. Lett. 1993, 81. (g) T. Osa, Y. Kashiwagi, Y. Yanagisawa, J. M. Bobbitt, J. Chem. Soc., Chem.Commun. 1994, 2535. (h) M. F. Semmelhack, C. R. Schmid, J. Am. Chem. Soc. 1983, 105, 6732. 16. World. Health. Organization.. World. Malaria. Report. 2011.:. http://www.who.int/malaria/world_malaria_report_2011/en/ 17. www3.niaid.nih.gov/topics/Malaria/understandingMalaria/facts.htm 18. www.cdc.gov/malaria/faq.htm 19. J. Schiller, G. Major, H. J. Koester, Y. Schiller, Nature 2000. 404, 285–289. 20. A.F. Slater, Pharmacology and Therapeutics. 1993, 57 (2–3), 203–235. 21. (a) S.R. Hawley, P.G. Bray, M. Mungthin, J.D. Atkinson, P.M. O'Neill, S.A. Ward, Antimicrobial Agents and Chemotherapy. 1998, 42 (3), 682–686. (b) C. Portela, C.M.M. Afonso, M.M.M. Pinto, M.J. Ramos, Bioorganic & Medicinal Chemistry. 2004, 12 (12), 3313–3321. (c) J.M. Karle, I.L. Karle, L. Gerena, W.K. Milhous, Antimicrobial Agents and Chemotherapy. 1992, 36 (7), 1538–1544. (d) F. Ayad, L. Tilley, L.W. Deady, Bioorganic & Medicinal Chemistry Letters. 2001, 11 (16), 2075–2077.. - 25 -.

(28) Okayama University 2012.9. 22. (a) T.J. Egan, Mini Reviews in Medicinal Chemistry. 2001, 1 (1), 113–123. (b) D.G. Spiller, P.G. Bray, R.H. Hughes, S.A. Ward, M.R. White, Trends in Parasitology. 2002, 18 (10), 441–444. (c) T.J. Egan, W.W. Mavuso, D.C. Ross, H.M. Marques, Journal of Inorganic Biochemistry. 1997, 68 (2), 137–145. (d) A. Leed, K. DuBay, L.M. Ursos, D. Sears, A.C. De Dios, P.D. Roepe, Biochemistry. 2002, 41 (32), 10245–10255. (e) P. Loria, S. Miller, M. Foley, L. Tilley, The Biochemical Journal. 1999, 339 (Pt 2), 363–370. 23. R. G. Ridley, Nature. 2002, 415, 686–693. 24. K. Cimanga, T. DeBruyne, L. Pieters, A. J. Vlietinck, C. A. Turger, J. Nat. Prod. 1997, 60, 688–691. 25. A. Paulo, E. T. Gomes, J. Steele, D. C. Warhurst, P. J. Houghton, Planta Med. 2000, 66, 30–34. 26. C. W. Wright, Plant derived antimalarial agents: new leads and challenges. Phytochem. Rev. 2005, 4, 55–61. 27. C. W. Wright, Recent developments in naturally derived antimalarials: cryptolepine analogues. J. Pharm. Pharmacol. 2007, 59, 899–904. 28. C. Bailly, W. Laine, B. Baldeyrou, M. C. De Pauw-Gillet, P. Colson, C. Houssier, K. Cimanga, S. Van Miert, A. J. Vlietinck,; L. Pieters, Anti-Cancer Drug Des. 2000, 15, 191–201. 29. (a) R. C. Larock, Comprehensive Organic Transformations, VCH: New York, 1989, pp 604–834. (b) M. Hudlicky, Oxidations in Organic Chemistry, ACS Monograph Ser. 186, American Chemical Society, Washington, DC, 1990, 114. (c) Comprehensive Organic Functional Group Transformations, (Eds.: A. R. Katritzky, O. Meth-Cohn, C. W. Rees, G. Pattenden, C. J. Moody), Elsevier Science: Oxford, 1995, Vols. 3 and 5. 30. (a) R. Siedlecka, J. Skarzewski, J. Michowski, Tetrahedron Lett. 1990, 31, 2177–2180. (b) A. E. J. de Nooy, A. C. Besemer, H. van Bekkum, Tetrahedron 1995, 51, 8023–8032. 31. M. Shibuya, M. Tomizawa, I. Suzuki, Y. Iwabuchi, J. Am. Chem. Soc. 2006, 128,. - 26 -.

(29) Okayama University 2012.9. 8412–8413. 32. Br2: (a) L. Farkas, B. Perlmutter, O. Schachter, J. Am. Chem. Soc. 1949, 71, 2829–2833; Br2 in acidic solution: (b) J. G. Mason, L. G. Baird, J. Am.Chem. Soc. 1972, 94, 6116–6119; HNO3–Br2: (c) F. Minisci, O. Porta, F. Recupero, C. Punta, C. Gambarotti, M. Pierini, L. Galimberti,. Synlett 2004, 2203–2205;. bis(quinuclidine)bromide(I) bromide: (d) L. K. Blair, N. B. Hobbs, L. Husband, N. Badika, J. Org. Chem. 1992, 57, 1600–1603; polymer-supported: (f) G. Yang, Z. Chen, S. Zang, J. Chen, Lizi Jiaohuan Yu Zifu 1998, 14, 475–480; Chem. Abstr. 1999, 130, 313445; polymeric DABCO–bromine complex: (g) J. A. Struss, W. D. Barnhart, M. R. Velasco, A. Bronley-DeLancey, Tetrahedron Lett. 2006, 47, 6635–6636. 33. Py∙HBr3: (a) M. P. Moon, Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons: Chichester, UK, 1995, Vol. 6, pp 4370–4373; Bu4NBr3: (b) M. J. L. Fournier, Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons: Chichester, UK, 1995, Vol. 7, pp 4738–4740; polymer-supported Py∙HBr3: (c) E. P. Koshya, J. Zachariasb, V. N. R. Pillai, React. Funct. Polym. 2006, 66, 845–850. 34. Z.-W. Mei, L.-J. Ma, H. Kawafuchi, T. Okihara, T. Inokuchi. Bull. Chem. Soc. Jpn. 2009, 82, 1000–1002. 35. Pyruvic acid: (a) R. M. C. Dawson, et al., Data for Biochemical Research, Oxford, Clarendon Press; Biotin: (b) B. J. Wisnieski, R. E. Williams, C. F. Fox, Proc. Nat. Acad. Sci. (U.S.A.) 1973, 70, 3669–3673; Dehydromucic Acid: (c) F. Koopman, N. Wierckx, J.H. de Winde and H.J. Ruijssenaars, Proc. Nat. Acad. Sci. USA. 2010, 107: 4919-4924; BAYX1005: (d) J. Y. Vanderhoek, R. W. Bryant, J. M. Bailey, J. Biol.. Chem. 1980, 255, 10064–10066. (e) R. Miiller-Peddinghaus, R. Fruchtmann, H.-J. Ahr, B. Beckermann, K. Btihner, B. Fugmann, B. Junge, M. Matzke, C. Kohlsdorfer, S. Raddatz, P. Theisen-Popp, K.-H. Mohrs, BAY X 1005, J. Lipid Mediators 1993, 6, 245–248; Naproxen: (f) A. P. Roszkowski, W. H. Rooks II, A. J. Tomolonis, L. M. Miller, J. Pharmacol. Exp. Ther. 1971, 179, 114–123.. - 27 -.

(30) Okayama University 2012.9. 36. D. L. Patrick, An Introduction to Medicinal Chemistry, Fourth Edition, 2009, pp 218. 37. (a) G. Tojo, M. Fernández, Oxidation of Primary Alcohols to Carboxylic Acids: A Guide to Current Common Practice, Springer, New York, 2006. (b) M. Cleij, A. Archelas, R. Furstoss, J. Org. Chem. 1999, 64, 5029. (c) J.-H. Xie, Z.-T. Zhou, W.-L. Kong, Q.-L. Zhou, J. Am. Chem. Soc. 2007, 129, 1868. (d) X. Li, B. List, Chem. Commun. 2007, 1739. 38. M. J. Schultz, M. S. Sigman, Tetrahedron 2006, 62, 8227. 39. Z.-W. Mei, T. Omote, M. Mansour, H. Kawafuchi, Y. Takaguchi, A. Jutand, S. Tsuboi, T. Inokuchi, Tetrahedron 2008, 64, 10761. 40. H. Yasuda, Y. Uenoyama, O. Nobuta, S. Kobayashi, I. Ryu, Tetrahedron Lett. 2008, 49, 367. 41. J. Lewkowski, ARKIVOC 2001, 17–54. 42. T, J. Egan, R. Hunter, C. H. Kaschula, H. M. Marques, A. Misplon, J. Walden, J. Med. Chem. 2000, 43, 283–291. 43. D. De, F. M. Krogstad, F. B. Cogswell, D. J. Krogstad, Am. J. Trop. Med. Hyg. 1996, 55, 579–583.. 44. D. De, F. M. Krogstad, L. D. Byers, D. J. Krogstad, J. Med. Chem. 1998, 41, 4918–4926.. - 28 -.

(31) Okayama University 2012.9. Chapter 2. High Performance and Selective Oxidation Method for Secondary Alcohols by Using of Organic Catalyst. - 29 -.

(32) Okayama University 2012.9. 2.1 Abstract. A new TEMPO-mediated catalytic oxidation method in combination with Py•HBr3 (stoichiometric) is developed for oxidation of secondary alcohols to the corresponding ketones. The performance of this oxidizing system is better compared with that of TEMPO method combined with R4NBr3. Poly (4-vinylpyridine) •HBr3 can be used in place of Py•HBr3. The electron-withdrawing substituent at the C-4 position of TEMPO increases the reactivity of TEMPO significantly in the oxidation of electron-deficient alcohols such as polyhaloalkylmethanols. Inductive effect of the substituent of TEMPO is discussed through the characterization of the redox potential of N–O radical by cyclic voltammetry.. OH Py HBr P Py HBr. EWG. N O (increased reactivity by EWG). Ar X. EWG X. O Py HBr3 P Py HBr3. EWG. HO N. Ar. Keywords: Oxidation, TEMPO, Co-oxidant, Redox, Cyclic voltammetry. - 30 -. X. EWG X.

(33) Okayama University 2012.9. 2.2 Introduction. Various oxidation methods of alcohols with metallic and non-metallic reagents,1 performed in a stoichiometric or catalytic manner,2,3 meeting with the demand in synthetic transformations have been developed. However, the examples of catalytic oxidation methods relied on non-metallic reagent are scarce in spite of increasing importance in view of green chemistry. In this context, the use of TEMPO in combination with a non-toxic co-oxidant4 is practically meaningful especially for process chemistry producing pharmaceutical substances,5 since the TEMPO is recoverable organic catalyst after the oxidation. In addition, the TEMPO and its N-oxoammonium intermediate, an active form for alcohol oxidation, can be featured by fair durability and safety in conducting the operation at ambient temperature.6 Although TEMPO is selective in the oxidation of primary hydroxy group in the presence of secondary ones,6c which is cumbersome to the oxidation of sterically hindered secondary alcohols. Accordingly, several modifications by reface of the reaction site of TEMPO have been devised in order to avoid steric repulsion in the nucleophilic addition of alcohol to the N-oxoammonium intermediate, as exemplified by using 2,2,6-trimethylpiperidine assembled in the adamantane framework7 or 2,6-dialkylpiperidine on the 9-azabicylo[3.3.1]nonane structure as well as its homologues,8. and. acyclic. derivatives.9. However,. the. activation. of. 2,2,6,6-tetramethylpiperidine-N-oxoammonium intermediate through an inductive effect of electron-withdrawing appendage at the C-4 position would be viable approach for a high performance oxidation of alcohols because of commercial availability of 4-hydroxyTEMPO. Although the effects of the substituent such CN and amides at the C-4 position of TEMPO was examined on reduction rate of ascorbate,10 the activation of the N-oxoammonium intermediate for oxidations based on the same protocol has not been attempted so far. Thus, we examined the effect of the substituent at the C4 position to attain smooth oxidations of secondary alcohols.. - 31 -.

(34) Okayama University 2012.9. Previously, we developed convenient catalytic oxidation methods of alcohols with TEMPO in combination with following activation procedures and co-oxidants: (a) electrooxidation in the presence of bromide ion,11a (b) aerobic oxidation in the presence of ruthenium catalyst,11b and cheap co-oxidants such as (c) NaBrO2,11c (d) R4NBr3,11d and (e) Ca(OCl)2.11c Now, we examined the use of pyridinium hydrobromide perbromide (Py•HBr3) as a co-oxidant,12a since this commercially available and stable reagent is less expensive than R4NBr3,12b and more advantageously polymer supported pyridinium hydrobromide perbromide is now available, though its oxidizing ability is not well characterized until now.13 Bromine and its amine complexes are capable of oxidation of alcohols, producing the corresponding carbonyls and thus far various methods and bromine-intercalated reagents have been developed.14,15 In general, the bromine-oxidation of alcohol proceeds slowly even with respect to electron rich secondary alcohols. Accordingly, in executing the catalytic oxidation of alcohols with TEMPO by the aid of Py•HBr3 (stoichiometric) as a co-oxidant, concurrent oxidation of the substrate with Py•HBr3 is issue to be discussed (Scheme 1).. 3-Py HBr3. OH R'. R. O R. 1. 2 O. 3-Py HBr3 R. R'. OH. + R. 4. H 5. X N O. O R. O. R. 6. 3 a, X = H b, X = MeO c, X = C6H5CO2 d, X = 4-CF3C6H4CO2 e, X = C6F5CO2. Scheme 1. TEMPO-mediated oxidation of alcohols with 3-Py HBr3.. - 32 -.

(35) Okayama University 2012.9. 2.3 Results and Discussion. 2.3.1 TEMPO-mediated oxidation of aliphatic secondary alcohols. We firstly examined the reactivity of Py•HBr3 as a co-oxidant in the TEMPO-mediated catalytic oxidation of secondary alcohols. As shown in Figure 1, the reaction of 2-undecanol (1a, R = C9H19, R' = CH3) with a mixture of 4-BzOTEMPO (3c,16 X = C6H5CO2, 10 mol%) and Py•HBr3 (1.5 equivalent) in a CH2Cl2-aqueous NaHCO3 system completes within 15 min to form the corresponding 2-undecanone (2a, R = C9H19, R' = CH3) in 99% (curve a). The amount of 3c can be reduced to 1 mol% for this conversion (curve b), though the reaction becomes somewhat sluggish. The oxidation of 1a to 2a, which is presumably due to oxidizing ability of Py•HBr3, was observed in the reaction system that lacks the presence of 3c (curve c), though being of no synthetic potential. Noteworthy is that the oxidation of 1a to 2a by the combination of 3c and R4NBr3 as co-oxidant proceeds much slower compared with Py•HBr3 (curve d).17. - 33 -.

(36) Conversion/%. Okayama University 2012.9. 100 90 80 70 60 50 40 30 20 10 0. (a). (b) (d) (c) 0. 5. 10. 15. 20. 25. 30. 35. 40. 45. 50. 55. 60. Time/min. Figure 1. Time-conversion curves for oxidation of 1a to 2a under varying the amount of 3c with Py HBr3 (1.5 equiv.) at 0-4 oC. Symbols are as follows: 3c, (a) = 10 mol%; 3c, (b) = 1.0 mol%; 3c, (c) = no addition; 3c, (d) = (10 mol%)-Bu4NBr3. Data points were obtained by GC analyses.. The present oxidizing system comprised of 3c (3~10 mol %) and Py•HBr3 (1.5 equivalent) was applied to the oxidation of various secondary alcohols 1. As shown in Table 1, most of secondary alcohols 1 can be oxidized at 0–4 °C, giving the corresponding ketones 2 in good yields. The reaction of sterically hindered alcohol such as menthol (1b) is best achieved at room temperature (entry 2). In place of chromate18 or Swern oxidation methods, 2-nitroalcohol 1g, accessible by Henry reaction, was smoothly oxidized to synthetically useful 2-nitroketone 2g by the present method, though a small of amount of bromination at the C-2 position was accompanied (ca. 5%, entry 7).. - 34 -.

(37) Okayama University 2012.9. Table 1. Oxidation of secondary alcohols with a combination of 4-BzOTEMPO (3c) and Py HBr3a 3cPy HBr3. OH R. CH2Cl2NaHCO3 0~4 oC. R' 1. Entry. O. Alcohol 1. 79 (78). R. b. 2c. Yield (%)b,d. O a, R = C9H19. R. 76. O. OH OH. O c. 3 HO. 93 O. OH 4. O. CO2Et. d. CO2Et. OH. 80 (64). e OH. O 84 (74). f. 6 N. N OH. O NO2. MeO. 81 (69). O. 5. 7. R' 2. Product 2. OH. 1. R. NO2. g. 87e. MeO. a. Carried out by the reaction of 1 (1 mmol) with 3c (5 mol%) and Py HBr3 (1.5~2 equiv.) at 0~4 oC. b Based on isolated products after column chromatography. c Carried out at room temperature. d Numbers in parenthesis are the data obtained with a 3cpoly(4-vinylPy) HBr3 system. e Bromination at the C-2 was accompanied (ca. 5%).. - 35 -.

(38) Okayama University 2012.9. In contrast to high performance in secondary alcohols, the oxidation of primary alcohol 4a (R = C10H21) with a 3c (catalytic)-Py•HBr3 (stoichiometric) system led to a mixture of the desired undecanal (R = C10H21, 5a) and the corresponding dimeric ester 6a in a ratio of 4:1 in 90% yield. For further insight into the effect of co-oxidant, two bromine compounds, i.e., Py•HBr3 and Bu4NBr3,11d were compared in the competitive oxidation of primary and secondary alcohols. As shown in Scheme 2, the oxidation of a mixture of 4a and 1a with a 3c-Py•HBr3 (1.0 equiv.) system produces a mixture of the corresponding aldehyde 5a, ketone 2a, and dimeric ester 6a in a ratio of 94:2:4, while the same run with a 3c-Bu4NBr3 (1.0 equiv.) system afforded 5a, selectively (5a/6a = 99:1). Thus, the problem forming dimeric ester 6a from primary alcohol with a 3c-Py•HBr3 can be avoided by employing the Bu4NBr3 as a co-oxidant.. O. 5a. OH. +. 3c-cooxidant (1.0 equiv.). 4a. O. + OH. 1a. CH2Cl2 NaHCO3 0~4 oC. 2a. + O O. (4a:1a = 1:1). 6a. Cooxidant. Product / ratio 5a : 2a : 6a. Py HBr3 Bu4NBr3. 94 : 2 : 4 99 : 1 : 0. Scheme 2. Competitive oxidation of primary and secondary alcohols.. Merit of Py•HBr3 as a co-oxidant lies in its easy extension to the polymer supported derivative,19 poly (4-vinylPy)•HBr3, which is commercially available. Thus, we examined the use of this polymer-supported reagent in place of Py•HBr3 and the results for oxidation of secondary alcohols are shown in the parenthesis of Table 1.. - 36 -.

(39) Okayama University 2012.9. Although slightly inferior results than that with Py•HBr3 are obtained with this supported reagent, the present TEMPO (3c)-mediated oxidation were smoothly performed and the solid pyridine support was recovered quantitatively only by filtration.. 2.3.2 TEMPO-mediated oxidation of aryl polyhaloalkyl alcohols. In the course of our study on synthesis of fluorine-containing building blocks (Scheme. 3),. we. met. with. somewhat. low. yields. in. the. oxidation. of. 1-aryl-2,2-dichloro-2-fluoroethyl alcohols 7 to the corresponding ketones 8 with conventional methods such as Swern and chromium(VI) oxidation.20 Since these unfavorable results seemed to be due to strong electron–withdrawing nature of dichlorofluromethyl group, we attempted to employ TEMPOs bearing an EWG group at the C4 position as an appendage which would result in enhancement of electronic polarity of reaction site of N-oxoammonium intermediate.. ArCHO. CFCl3/ Sn. OH CFCl2. Ar. Oxid. Zn/ AcOH. O Ar. 7. CFCl2. O Ar. CHFCl. 8. Scheme 3. Synthesis of -fluoroketones from fluorohaloalkanes.. Thus, effect of the appendage on TEMPOs is examined by dictating the time-course of the conversion of 7a (Ar = C6H5) to 8a (Ar = C6H5) by changing kind of substituent at the C-4 position. As shown in Figure 2, the oxidation of 7a is fairly facilitated by appendage of an arenecarboxy group on TEMPO, curves (c), (d), and (e), compared with the TEMPO bearing no appendage, curve (a). Among them, the most favorable conversion was attained with the 4-(4-trifluoromethylbenzoyl)-substituted 3d (curve (d)), prepared by 4-trifluoromethylbenzoylation of 4-hydroxyTEMPO. Similar. - 37 -.

(40) Okayama University 2012.9. enhancement in the conversion was also observed in the oxidation of 2-octanol, being classified as electron-rich alcohol compared with 2,2-dichloro-2-fluroethyl derivatives, in which the best conversion was also attained with 3d.. 100 90. (d). Conversion/%. 80 70. (c). (e). 60. (b). 50. (a). 40 30 20 10 0 0. 10. 20. 30. 40. 50. 60. 70. 80. 90 100 110 120. Time/min. Figure 2. Time-conversion curves for oxidation of 7a to 8a under various TEMPO catalysts 3a-d. Carried out by reaction of 7a (1 mmol) with 3 (5 mol%) and Py HBr3 (1.5~2 equiv.) at room temperature. Symbols are as follows: (a) = 3a, (b) = 3b, (c) = 3c, (d) = 3d, and (e, dotted line) = 3e. Data points were obtained by GC analyses.. Based on these results, we next attempted the oxidation of carbinol with an electron-withdrawing group. As shown in Table 2, the dichlorofluoro and dichlorotrifluoromethyl, dichlorocarboxy alcohols21 are cleanly oxidized under the conditions developed above.. - 38 -.

(41) Okayama University 2012.9. Table 2. Oxidation of (aryl)polyhaloalkylmethanols with a combination of 4-(4-CF3BzO)TEMPO (3d) and Py HBr3a OH Ar. EWG Hal Hal. Entry. Alcohol. 1 2 3 4. F. 91 94 92 93. 9a 9b. C6H5 4-MeOC6H5. 10a 10b. 69 86. Cl 11a CO2Me 11b. C6H5 4-MeOC6H5. 12a 12b. 79 78. Ar F. 9 10. F 13a CO2Et 13b. C6H5 4-MeOC6H5. 14a 14b. 80 72. 11. 4-MeOC6H5. 16. 70. Cl CF3. Ar. HO. HO Ar HO. CF3 Ar. b Product Yield (%). 8a 8b 8c 8d. Ar. Cl 7 8. Ar =. EWG Hal Hal. C6H5 4-MeOC6H5 4-ClC6H5 4-MeC6H5. HO. HO. CH2Cl2-NaHCO3. Ar. 7a 8b 8c 8d. Cl Cl. Cl 5 6. O. 3d-Py HBr3. 15. a. Carried out by reaction of polyhalocarbinol (1 mmol) with 3d (5 mol%) and Py HBr3 (1.5~2 equiv.) at room temperature. b Isolated yield based on separated products.. - 39 -.

(42) Okayama University 2012.9. 2.3.3 Characterization of redox properties of C4-substituted TEMPOs. The enhanced reactivity of the electronically activated TEMPOs was rationalized by the characterization of their redox properties. The cyclic voltammetry of C4-substituted TEMPOs (3a-e) was performed in dichloromethane, the same solvent as in the catalytic reactions. All exhibited an oxidation peak and the reduction peak of C4-substituted TEMPO+ on the reverse scan, in a reversible system at the scan rate of 0.5 Vs-1 (Table 3). From the potentials values, it emerges that the redox properties of C4-substituted TEMPOs are affected by the electronic properties of the substituents. The oxidation peak potentials of TEMPOs substituted by ester groups (3c-e) are very similar and are more positive than for H and OMe substituents (3a, b). The reduction peak potentials of their oxidized forms, N-O+ are also more positive for esters substituents. Consequently, the TEMPO+ substituted by the esters groups at the C4 position generated by the oxidation of the C4-substituted TEMPOs (3c-e) are more powerful oxidants for the oxidation of alcohols than those substituted by H or MeO. This is in agreement with the results of the catalytic reactions in which Py•HBr3 acts as an oxidant for the TEMPOs.. - 40 -.

(43) Okayama University 2012.9. Table 3. Oxidation peak potentials of C4-Z-substituted TEMPO (2 mM) in CH2Cl2 (containing nBu4NBF4, 0.3 M) and reduction peak potentials of C4-Z-substituted TEMPO+.. 3. Z. Z-TEMPO. Z-TEMPO+. Epox. Epred. E0. (V vs SCE)a. (V vs SCE)a. (V vs SCE)a. a. H. +0.852. +0.766. +0.809. b. MeO. +0.885. +0.803. +0.844. c. C6H5CO2. +0.970. +0.887. +0.928. d. 4-CF3-C6H4CO2. +0.966. +0.885. +0.925. e. C6F5CO2. +0.974. +0.886. +0.930. a) Potentials were determined at a gold disk electrode (d = 0.5 mm), at the scan rate of 0.5 V -1 at 22 oC.. - 41 -.

(44) Okayama University 2012.9. 2.4 Conclusion. In summary, a high performance oxidation method of alcohols with TEMPO substituted with an EWG at the C-4, which is useful for the electron-deficient secondary alcohols such as ArCH(OH)CFCl2, has been developed by using Py•HBr3 as a co-oxidant. Reactivity of Py•HBr3 was discussed in terms of efficiency and selectivity in comparison with similar bromine compounds such as Bu3NBr3, and the method was easily extended to the polymer supported bromine reagents as a co-oxidant.. Inductive. activation. of. TEMPO. by. the. appendage. of. electron-withdrawing group at the C4 position was shown to facilitate the reaction rate, which was rationalized by measuring the cyclic voltammetry of the 4-substituted TEMPOs.. - 42 -.

(45) Okayama University 2012.9. 2.5 Experimental Section. 2.5.1 General. IR spectra were obtained with a Shimazu, Model FT-IR 8400, and only major absorptions are cited. 1H,. 13. C, and. 19. F NMR spectra were recorded on Varian. instruments with CDCl3 as a solvent unless otherwise indicated.. 2.5.2 General procedure for oxidation of secondary alcohols to the ketones. OH R. 3cPy HBr3 CH2Cl2NaHCO3 0~4 oC. 1a, R = C9H19. O R 2a, R = C9H19. A solution of 2-undecanol (1a, 172 mg, 1 mmol) and 3c (28 mg, 0. 1 mmol) in CH2Cl2 (6 mL) was covered with aqueous saturated NaHCO3 (12 mL). To this biphase mixture was added portionwise Py•HBr3 (480 mg, 1.5 mmol) under a vigorous stirring at 0–4 °C. The mixture was stirred for an additional 30 min. The reaction was quenched with aqueous 5% Na2S2O3. The products were extracted with CH2Cl2 and the aqueous layer was again extracted with AcOEt. Extracts were washed separately with aqueous NH4Cl, dried (MgSO4), and concentrated. The combined crude product was purified by column chromatography (SiO2, hexane-AcOEt 10:1 to 5:1) to give 135 mg (79% yield) of 2a (Rf = 0.79, hexane-AcOEt 3:1); IR (neat): 1719, 1466, 1410, 1358, 1228, 1163, 758, 719 cm-1; 1H NMR (300 MHz):  0.87 (t, J = 7.4 Hz, 3H), 1.26 (brs, 12H), 1.56 (m, 2H), 2.13 (s, 3H), 2.41 (t, J = 7.4 Hz, 2H); 13C NMR (75.5 MHz): . , 208.9.. - 43 -.

(46) Okayama University 2012.9. O. O 2c. 4,4'-Bicyclohexanone (2c): Yield 93% (Rf = 0.47, hexane-AcOEt 1:2); mp 113-115 °C (from hexane) (lit.22 112-116 °C); IR (KBr): 1705, 1464, 1439, 1418, 1354, 1333, 1321, 1302, 1281, 1267, 1244, 1215, 1167, 1155, 1115, 1069, 1011, 980, 932, 858, 816, 762, 704 cm-1; 1H NMR (300 MHz):  1.45–1.60 (m, 4H), 1.63–1.79 (m, 2H), 2.02–2.12 (m, 4H), 2.27–2.46 (m, 8H);. 13. C NMR (75.5 MHz): . 211.0 (2C).. O CO2Et. 2d. Ethyl 2-Oxo-4-phenylbutanoate (2d): Yield 81% (Rf = 0.5, hexane-AcOEt 5:1); IR (neat): 1728, 1605, 1497, 1454, 1400, 1370, 1304, 1271, 1250, 1190, 1067, 1030, 856, 750, 700 cm-1; 1H NMR (300 MHz):  1.35 (t, J = 7.1 Hz, 3H), 2.96 (t, J = 7.7 Hz, 2H), 3.18 (t, J = 7.7 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 7.18–7.32 (m 5H);. C NMR (75.5 MHz): . 13. 125.9, 127.9 (2C), 128.1 (2C), 139.6, 160.4, 192.8.. O. N 2f. 3-Pentanoylpyridine (2f): Yield 84% (Rf = 0.41, hexane-AcOEt 1:1); IR (neat): 1690, 1586, 1466, 1458, 1420, 1374, 1350, 1269, 1223, 1117, 1011, 970, 797, 704 cm-1; 1H NMR (300 MHz):  0.94. - 44 -.

(47) Okayama University 2012.9. (t, J = 7.9 Hz, 3H), 1.41 (m, 2H), 1.72 (m, 2H), 2.97 (t, J =7.2 H, 2H), 7.41 (d,d,d, J = 7.9, 4.7, 1.1 Hz, 1H), 8.23 (d,d,d, J = 7.9, 2.2, 2.2 Hz, 1H), 8.76 (d,d, J = 4.9, 1.6 Hz, 1H), 9.15 (d, J = 2.2 Hz, 1H); 13C NMR (75.5 MHz):  132.2, 135.1, 149,4, 153.1, 198.9.. 2-Nitro-1-(4-methoxyphenyl)propanone (2g) and 2-bromo-2-nitro-1-(4-methoxy phenyl)propanone (byproduct): O NO2 MeO 2g. 2g: yield 87% (Rf = 0.31, hexane-AcOEt 3:1); IR (neat): 3534, 2843, 1686, 1601, 1560, 1512, 1452, 1389, 1364, 1325, 1269, 1229, 1175, 1123, 1026, 966, 845, 752, 683 cm-1; 1H NMR (300 MHz) (absorptions based on major isomer) 23:  1.82 (d, J = 7.1 Hz, 3H), 3.90 (s, 3H), 6.13 (q, J =7.1 H, 2H), 6.99 (d, J = 8.8 H, 2H), 7.94 (d, J = 8.8 H, 2H); 13C NMR (75.5 MHz) (absorptions based on major isomer):  84.5, 114.4 (2C), 126.4, 131.2 (2C), 164.8, 188.1.. O. NO2 Br. MeO. 2-Bromo-2-nitro-1-phenylpropanone: yield 5% (Rf = 0.65, hexane-AcOEt 3:1); IR (neat): 2843, 1686, 1601, 1560, 1512, 1458, 1441, 1424, 1381, 1333, 1317, 1258, 1180, 1140, 1121, 1080, 1028, 957, 845 cm-1; 1H NMR (300 MHz):  2.49 (s, 3H), 3.88 (s, 3H), 6.92 (d, J = 9.1 H, 2H), 7.94 (d, J = 9.1 H, 2H); 13C NMR (75.5 MHz):  30.2, 55.6, 92.2, 114.2 (2C), 123.8, 132.1 (2C), 164.4, 183.1.. 2.5.3 Time-course for the oxidation of 2a with a 3c-cooxidants system. - 45 -.

(48) Okayama University 2012.9. A mixture of 1a (172 mg, 1 mmol), 3c (28 mg, 0. 1 mmol), and Py•HBr3 (480 mg, 1.5 mmol) in CH2Cl2 (6 mL)-aqueous saturated NaHCO3 (12 mL) was allowed to react and the aliquots at the prescribed time were analyzed by GC and the selectivity was calculated based on the peak areas (Figure 1). Similarly, the time-course of the oxidation of 7a was achieved by using Py•HBr3 in combination with various 3a-d (Figure 2).. 2.5.4 A typical procedure for oxidation of secondary alcohols to the ketones with poly(4-vinylPy)•HBr3. A solution of 1a (86 mg, 0.5 mmol) and 3c (28 mg, 0. 1 mmol) in CH2Cl2 (3 mL) was covered with aqueous saturated NaHCO3 (6 mL). To this biphase mixture was added portionwise poly(4-vinylpyridinium tribromide) (300 mg) under a vigorous stirring at room temperature. The stirring was continued at room temperature until 1a was consumed, for about 2 h as monitored with TLC. The mixture was filtered off to leave poly(4-vinylpyridine) (107 mg) and the filtrate was worked up in the usual manner to give 67 mg (78% yield) of 2a after purification by column chromatography.. 2.5.5. Preparation. of. 4-(4-trifluoromethylbenzoyloxy)-2,2,6,6-tetramethyl. piperidine-1-oxyl (3d). Z. O N. 3d, Z=4-CF3-C6H4CO2. To a solution of 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (1.72 g, 10 mmol) and pyridine (1.62 mL, 20 mmol) in THF (10 mL) was added dropwise a solution of 4-trifluoromethylbenzoyl chloride (1.63 mL, 11 mmol) in THF (3 mL) at 0–4 °C. The mixture was stirred at room temperature overnight and worked up in the usual manner. The crude product was purified by column chromatography (SiO2, hexane-AcOEt. - 46 -.

(49) Okayama University 2012.9. 10:1 to 5:1) to give 3.2 g (93% yield) of 3d as solids: mp 74–75°C (from hexane) (Rf = 0.55 hexane-AcOEt 3:1); IR (KBr): 1721, 1585, 1512, 1466, 1412, 1331, 1283, 1242, 1167, 1138, 1128, 1101, 1067, 1017, 963, 862, 775, 705 cm-1; 1H NMR, treated with PhNHNH2 (300 MHz):  1.176 and 1.181 (s, 12H), 1.68 (m 2H), 1.94-2.00 (m, 2H), 5.23 (m, 1H), 7.60 (d, J = 8.2 Hz, 2H), 8.03 (d, J = 8.24 Hz, 2H);. 19. F NMR,. treated with PhNHNH2 (282.3 MHz):  –63.3 (s). HRMS (ESI) calcd for C11H14NO4 (MH+) 224.0923, found 224.0928 (MH+). HRMS (ESI) calcd for C17H21F3NO3 (M+) 344.1474, found 344.1499 (M+).. 2.5.6. Preparation. of. 4-(2,3,4,5,6-pentafluorobenzoyloxy)-2,2,6,6-tetramethyl. piperidine-1-oxyl (3e). Z. O N. 3e, Z=C6F5CO2. Compound 3e was prepared by the reaction of 2,3,4,5,6-pentafluorobenzoic acid and 4-hydroxy-2,2,6,6-tetramethylpiperinine-1-oxyl in the presence of carbon tetrabromide, PPh3, pyridine in CH2Cl2: mp 102–104 °C (from hexane-AcOEt 10:1) (Rf = 0.64 hexane-AcOEt 3:1); IR (KBr): 1728, 1651, 1526. 1495, 1416, 1368, 1337, 1232, 1177, 1107, 1092, 1069, 1007, 957, 770 cm-1; 1H NMR, treated with PhNHNH2 (300 MHz):  1.152 and 1.158 (s, 12H), 1.64 (m 2H), 1.93-1.99 (m, 2H), 5.24 (m, 1H); 19. F NMR, treated with PhNHNH2 (282.3 MHz):  –160.6 (m), –149.0 (m), –138.9 (m).. HRMS (ESI) calcd for C11H14NO4 (MH+) 224.0923, found 224.0928 (MH+). HRMS (ESI) calcd for C16H17F5NO3 (M+) 366.1129, found 366.1121 (M+).. 2.5.7 Electrochemical set-up and electrochemical procedure for cyclic voltammetry. Cyclic voltammetry was performed with a home made potentiostat and a. - 47 -.

(50) Okayama University 2012.9. wave-form generator, PAR Model 175. The cyclic voltammograms were recorded on a Nicolet 3091 digital oscilloscope. Experiments were carried out in a three-electrode cell. The working electrode was a steady gold disk electrode (d = 0.5 mm). The counter electrode was a platinum wire of ca 1 cm2 apparent surface area. The reference was a saturated calomel electrode separated from the solution by a bridge filled by 2 mL of dichloromethane containing nBu4BF4 (0.3 M). 15 mL of distilled and degassed dichloromethane containing nBu4BF4 (0.3 M) was poured into the cell, followed by 4.68 mg (0.03 mmol, 2 mM) of TEMPO (3a). The cyclic voltammetry was performed at the scan rate of 0.5 Vs-1 in the potential range between 0 and +1.2 V. Similar experiments were performed from 3b (5.6 mg), 3c (8 mg), 3d (10 mg), 3e (11 mg).. 2.5.8 General procedure for oxidation of polyhaloalkyl alcohols to the ketones with 3d-Py•HBr3. OH Cl. MeO. CF3 Cl. O. 3d-Py HBr3 CH2Cl2-NaHCO3. Cl. MeO. 9b. CF3 Cl. 10b. A solution of 2,2-dichloro-3,3,3-trifluoro-1-(4-methoxyphenyl)propanol18 (9b, 288 mg, 1.0 mmol) and 4-(4-CF3C6H4CO2)TEMPO (3d, 35 mg, 0.1 mmol) in CH2Cl2 (6 mL) was covered with aqueous 5% NaHCO3 (12 mL). To this biphase mixture was added portionwise Py•HBr3 (480 mg, 1.5 mmol) under a vigorous stirring at room temperature. The mixture was stirred for an additional 1.5 h and the reaction was quenched with aqueous 5% Na2S2O3 (5 mL). The products were extracted with CH2Cl2 and the aqueous layer was again extracted with AcOEt. Extracts were separately washed with brine, dried (MgSO4), and concentrated. The combined crude product was purified by column chromatography (SiO2, hexane-AcOEt 10:1 to 3:1) to. - 48 -.

(51) Okayama University 2012.9. give 245 mg (86% yield) of 10b (Rf = 0.65, hexane-AcOEt 5:1): IR (neat): 2845, 1697, 1601, 1574, 1512, 1460, 1425, 1316, 1261, 1207, 1180, 1124, 1045, 1026, 930, 870, 847, 829, 737, 702, 673 cm-1; 1H NMR (300 MHz):  3.91 (s, 3H), 6.97 (d, J = 9.2 Hz, 2H), 8.27 (d, J = 9.2 Hz, 2H); 13C NMR (75.5 MHz):  55.5, 78.7 (q, 2JCF = 31.1 Hz), 113.8 (2C), 121.3 (q, 1JCF = 283.3 Hz), 122.7, 133.4 (2C), 164.7, 181.3;. 19. F NMR. (282.3 MHz):  –75.2 (s).. O Cl. CO2Me Cl. 12a. Methyl 2,2-Dichloro-3-oxo-3-phenylpropanoate (12a): Yield 79% (Rf = 0.53, hexane-AcOEt 5:1); IR (neat): 2957, 1769, 1746, 1713, 1690, 1597, 1449, 1437, 1252, 1217, 1186, 1015, 864, 824, 795, 689 cm-1; 1H NMR (300 MHz):  3.87 (s, 3H), 7.45–7.52 (m, 2H), 7.60–7.65 (m, 1H), 8.02–8.07 (m, 2H); 13C NMR (75.5 MHz): 54.8, 81.6, 128.6 (2C), 130.0 (2C), 130.8, 134.1, 164.5, 183.3. HRMS (ESI) calcd for C10H9Cl2O3 (MH+) 246.9929, found 246.9887 (MH+).. O Cl. MeO. CO2Me Cl. 12b. Methyl 2,2-Dichloro-3-oxo-3-(4-bromophenyl)propanoate (12b): Yield 78% (Rf = 0.62, hexane-AcOEt 5:1); IR (neat): 1769, 1746, 1713, 1690, 1584, 1485, 1437, 1398, 1250, 1217, 1184, 1074, 1007, 928, 868, 824, 760, 725 cm-1; 1H NMR (300 MHz):  3.89 (s, 3H), 7.63 (d, J = 8.8 Hz, 2H), 7.92 (d, J = 8.8 Hz, 2H); C NMR (75.5 MHz):  55.0. 81.4, 129.6, 129.7, 131.5 (2C), 132.1 (2C), 164.3,. 13. 182.7. HRMS (ESI) calcd for C10H7BrCl2O3 (MH+) 324.9034, found 324.8992 (MH+).. - 49 -.

(52) Okayama University 2012.9. O F. MeO. CO2Et F. 14b. Ethyl 2,2-Difluoro-3-(4-methoxyphenyl)-3-oxopropanoate (14b): Yield 72% (Rf = 0.59, hexane-AcOEt 5:1); IR (neat): 2845, 1771, 1694, 1690, 1600, 1573, 1514, 1464, 1447, 1427, 1395, 1373, 1316, 1269, 1182, 1159, 1122, 1099, 1076, 1026, 924, 910, 847, 791, 712, 698 cm-1; 1H NMR (300 MHz):  1.32 (t, J = 7.1 Hz, 3H), 3.90 (s, 3H), 4.38 (q, J = 7.1 Hz, 2H), 6.98 (d, J = 9.1 Hz, 2H), 8.07 (d, J = 9.1 Hz, 2H); 13C NMR (75.5 MHz): . 1. JCF = 264.3 Hz), 114.3. (2C), 124.0, 132.5 (t, 4JCF = 2.9 Hz) (2C), 162.0 (t, 2JCF = 30.5 Hz), 165.1, 183.8 (t, 2. JCF = 27.1 Hz);. 19. F NMR (282.3 MHz):  –107.6 (s). HRMS (ESI) calcd for. C12H13F2O4 (MH+) 259.0782, found 259.0749 (MH+).. - 50 -.

(53) Okayama University 2012.9. References and Notes. 1.. Hudlicky, M. Oxidation in Organic Chemistry; ACS Monograph 186; American Chemical Society, Washington DC, 1990, pp114–159.. 2.. Reviews; Chromium reagent: (a) Ley, S. V.; Madin, A. Comprehensive Organic Synthesis; Pergamon: New York, 1991; Vol. 7, pp 251–289. Other Metallics: (b) Procter, G. Comprehensive Organic Synthesis; Pergamon: New York, 1991; Vol. 7, pp 305–327. DMSO: (c) Lee, T. V. Comprehensive Organic Synthesis; Pergamon: New York, 1991; Vol. 7, pp 291–303.. 3.. Schultz, M. J.; Sigman M. S. Tetrahedron 2006, 62, 8227–8241, and references cited therein.. 4.. (a) Lenoir, D. Angew. Chem. Int. Ed. 2006, 45, 3206–3210. (b) Liu, R.; Liang, X.; Dong, C.; Hu, X. J. Am. Chem. Soc. 2004, 126, 4112–4113, and references cited therein.. 5.. Song, Z. J.; Zhao, M.; Desmond, R.; Devine, P.; Tschaen, D. M.; Tillyer, R.; Frey, L.; Heid, R.; Xu, F.; Foster, B.; Li, J.; Reamer, R.; Volante, R.; Grabowski, E. J.; Dolling, U. H.; Reider, P. J.; Okada, S.; Kato, Y.; Mano, E. J. Org. Chem. 1999, 64, 9658–9667.. 6.. TEMPO oxidation, reviews: (a) Vogler, T.; Studer, A. Synthesis 2008, 1979–1993. (b) Adam, W.; Saha-Möller, C. R.; Ganeshpure, P. A. Chem. Rev. 2001, 101, 3499–3548. (c) de Nooy, A. E. J.; Besemerm A. C.; van Bekkum, H. Synthesis 1996, 1153–1174. (d) Inokuchi, T.; Matsumoto, S.; Torii, S. J. Synth. Org. Chem. Jpn. 1993, 51, 910-920.. 7.. (a) Shibuya, M.; Tomizawa, M.; Suzuki, I.; Iwabuchi, Y. J. Am. Chem. Soc. 2006, 128, 8412–8413. (b) Dupeyre, R. M.; Rassat, A. Tetrahedron Lett. 1973, 14, 2699–2701.. 8.. (a) Demizu, Y.; Shiigi, H.; Oda, T.; Matsumura, Y.; Onomura, O. Tetrahedron Lett. 2008, 49, 48–52. (b) Dupeyre, R. M.; Rassat, A. J. Am. Chem. Soc. 1966, 88,. - 51 -.

(54) Okayama University 2012.9. 3180–3181. Reviews: (c) Keana, J. F. W. Chem. Rev. 1978, 78, 37–64. (d) Rozantsev, E. G.; Sholle, V. D. Synthesis 1971, 401–414. 9.. Kashiwagi, Y.; Nishimura, T.; Anzai, J. Electrochim. Acta 2002, 47, 1317–1320.. 10. Morris, S.; Sosnovsky, G.; Hui, B.; Huber, C. O.; Rao, N. U. M.; Swartz, H. M. J. Pharm. Sci. 1991, 80, 149–152. 11. (a) Inokuchi, T.: Matsumoto, S.; Torii, S. J. Org. Chem. 1991, 56, 2416–2421. (b) Inokuchi, T.; Nakagawa, K.; Torii, S. Tetrahedron Lett. 1995, 36, 3223–3226. (c) Inokuchi, T.: Matsumoto, S.; Nishiyama, T.; Torii, S. J. Org. Chem. 1990, 55, 462–466. (d) Inokuchi, T.: Matsumoto, S.; Fukushima, M.; Torii, S. Bull. Chem. Soc. Jpn. 1991, 64, 796–800. 12. Py•HBr3: (a) Moon, M. P. Encyclopedia of Reagents for Org. Synth. 1995, 6, pp 4370–4373. Bu4NBr3 (b) Fournier, M. J. L. Encyclopedia of Reagents for Org. Synth. 1995, 7, pp 4738–4740. 13. Koshya, E. P.; Zachariasb, J.; Pillai, V.N. R. Reactive and Functional Polymers, 2006, 66, 845–850. 14. For secondary OH; Br2 in acidic solution: (a) Mason, J. G.; Baird, L. G. J. Am. Chem. Soc. 1972, 94, 2829–2833. Br2-AgOAc: (b) Roscher, N. M.; Jedziniak, E. J. Tetrahedron Lett. 1973, 1049–1052. Br2 by electrolysis: (c) Takaguchi, T.; Nonaka, T. Bull. Chem. Soc. Jpn. 1987, 60, 3137–3142. Br2/light for ClCH2COCH2Cl: (d) Turner, P. J.; Routledge, V. I.; Jeff. M. Eur. Pat. Appl. EP 260,054 (Cl. C07C45/30); Chem. Abstr. 1988, 109, 109863d. Bis(quinuclidine)bromide(I) bromide: (e) Blair, L. K.; Hobbs, N. B.; Husband, L.; Badika, N. J. Org. Chem. 1992, 57, 1600–1603.. Polymer-supported: (f) Yang,. G.; Chen, Z.; Zang, S.; Chen, J. Lizi Jiaohuan Yu Zifu 1998, 14, 475–480; Chem. Abstr. 1999, 130, 313445g.. Polymeric DABCO-bromine complex: (g) Struss, J.. A.; Barnhart, W. D.; Velasco, M. R.; Bronley-DeLancey, A. Tetrahedron Lett. 2006, 47, 6635–6636.. - 52 -.

(55) Okayama University 2012.9. Chapter 3. Green Procedure for Preparation of Carboxylic Acids by TEMPO Oxidation of Primary Alcohols. - 53 -.

(56) Okayama University 2012.9. 3.1 Abstract. Expeditious and benign methods for primary alcohol-carboxylic acid conversions with TEMPO were developed in a biphasic system composed of a slightly miscible ether (THP) and aqueous layer. Easily available co-oxidants such as Py•HBr3, Bu4NBr3,. and. electro-oxidation. were. successfully. applied. N-oxoammonium species as a recyclable catalyst.. ether solvent. R. OH. TEMPO (cat.) Py•HBr3. PTC aqueous layer NaHCO3. Keywords: Oxidation, TEMPO, Co-oxidant, Ether. - 54 -. R. OH O. to. generate.

(57) Okayama University 2012.9. 3.2 Introduction. Oxidation of alcohols to the corresponding carboxylic acids is a fundamental operation in organic chemistry.1,2 TEMPO oxidations, achieved in a catalytic manner in coordination with stoichiometric amount of co-oxidants, have been recognized to be inherently benign and useful for selective transformations of alcohols.3 Conventionally, TEMPO oxidations are executed in an aqueous-organic two-phase system and moderately or highly water-miscible solvents such as CH2Cl2 and acetonitrile are often employed.4 Inspired by recent development in devising environmentally friendly procedures,5 we further examined the improvement of TEMPO oxidation by tuning the reaction media to replace harmful solvents and by changing the co-oxidant. Thus, ethereal solvents like tetrahydropyran (THP)6 were employed as the organic layer of a two-phase system for the exhaustive conversion of primary alcohols to carboxylic acids. In this respect, easy recoverability after reaction and stability toward air-oxidation of the ethereal solvent should be a criteria for practical application.. - 55 -.

(58) Okayama University 2012.9. 3.3 Results and Discussion. 3.3.1 Catalytic oxidation of primary alcohols with a combination of 4-BzOTEMPO (5) and Py•HBr3. We employed 4-benzoyloxy-2,2,6,6-tetramethyl-piperidine-1-oxyl (4-BzOTEMPO, 5) for the recyclable catalyst from various TEMPO derivatives because 5 is slightly activated by the electron-withdrawing benzoyloxy group at the C4 position.7 As the first step, we examined the oxidation of 1a with a combination of 5 (5 mol%) and a co-oxidant in THP-aqueous saturated NaHCO3 (1:1 v/v) containing a quaternary ammonium salt such as BenzylEt3NCl and acetylcholine chloride as a phase-transfer catalyst (PTC). Thus, the addition of Py•HBr3 (3 equiv.) as a co-oxidant to the reaction media afforded the corresponding carboxylic acid 3a in 91% yield and formation of dimeric ester 4a was negligible (~1%). The presence of quaternary ammonium salts in the two-phase system was not crucial in comparison with a run without these reagents, since pyridinium salts in this reaction media could participate as a PTC.4d. 5 Py•HBr3. OH. CHO THP NaHCO3. 1a. 2a. CO2H. +. +. 3a. OBz CO2 N O. 4a 5. Scheme 1. Catalytic oxidation of primary alcohols with a combination of 4-BzOTEMPO (5) and Py HBr3. - 56 -.

(59) Okayama University 2012.9. 3.3.2 Optimized reaction conditions. Subsequently, we surveyed suitable ethereal solvents in addition to THP for the two-phase system, and the following results were obtained in the oxidation of 1a to 3a: cyclopentyl methyl ether (CPME) (80%), tetrahydrofuran (THF) (80%), diisopropyl ether (67%), methyl tert-butyl ether (89%), and CH2Cl2 (77%). It appears that solvents slightly miscible in water are useful as an organic layer.8 However, among these solvents, THP should be the best in terms of high yield, easy handling, and recoverability. Furthermore, Yasuda, Ryu, et al. have recently demonstrated the excellent stability of THP towards hydrogen abstraction from the oxygen-substituted carbon, as compared with THF, as a result of their study on tributyltin hydride-mediated radical cyclization.9 This finding favors the use of THP since it is less likely to form peroxide with oxygen during TEMPO oxidation. Subsequently, we searched for a favorable co-oxidant for the conversion of 1a to 3a in a two-phase system comprised of THP-aqueous NaHCO3. As shown in Table 1, entries 3~5, it turns out that bromine salts such as Py•HBr3,7 Bu4NBr3,10 and electrolysis with bromide ion11 are the appropriate choice of co-oxidizing reagent because of high yield and high catalytic performance. The runs employing NaOCl4e and Ca(OCl)210 in combination with KBr were less effective than those with the above bromine compounds (entries 1 and 2).. - 57 -.

(60) Okayama University 2012.9. Table 1. Search for Co-oxidant in TEMPO-mediated oxidation of 1a to 3a.a. 1a. 4-BzOTEMPO (5) Co-oxidant. entry. Co-oxidant. 1 2 3 4 5. NaOCl (6) Ca(OCl)2 (4.5) Py HBr3 (3) Bu4NBr3 (3) Electrolysis (10 F)c. 2a +. 3a. Product, %b 3a 2a 33 59 87 72 84. 48 23 -trace trace. a. Carried out with 5 and co-oxidant in THP (8 mL)sat. NaHCO3 (8 mL) in the presence of PTC. b Based on the isolated products. c Electricity passed.. This reaction can be performed on a scale of 15 mmol of 1a in THP (120 mL)-aqueous NaHCO3 (120 mL) in the presence of PTC at room temperature for 5 h, giving 3a in 91% yield, in which 83% of THP used for the reaction media and workup solvent was recovered on a rotary evaporator after separation of the aqueous layer. As shown in Table 2, the present method can readily be applied not only to aliphatic primary alcohols 1 including acyclic (entries 1, 2, and 6) and cyclic structures (entry 5), but also to aromatic (entries 3 and 4) and hetero aromatic alcohols (entry 7), producing the corresponding carboxylic acids 3 respectively. The oxidation of 5-(hydroxymethyl)-2-furaldehyde (HMF, 1h), a value-added chemical available from biomass,12 leads selectively to 5-formyl-2-furancarboxylic acid (3h),13,14 useful as a precursor of 2,5-furandicarboxylic acids. Carbohydrate derivatives 1i, j with primary hydroxy groups are easily oxidized to the corresponding uronic acids 3i, j in good yields (entries 8 and 9).. - 58 -.